Glucose Induces MafA Expression in Pancreatic Beta Cell Lines via the Hexosamine Biosynthetic Pathway

Vanderford, Nathan L.; Andrali, Sreenath S.; Özcan, Sabire

doi:10.1074/jbc.m605064200

Cited by 56 publications

(62 citation statements)

References 75 publications

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“…It is in large part regulated by the flux of glucose through the HBP and generation of UDP-GlcNAc, which in β-cells is proportional to the extracellular glucose concentration (30). In β-cells O-GlcNAcylation mediate the induction of MafA expression by glucose (21) and the subcellular distribution of BETA2 (31). Here, we show that glucose increases O-GlcNAcylation of Pdx-1, but not BETA2, in the nucleus and its recruitment to the GPR40 promoter.…”

Section: Discussionmentioning

confidence: 81%

“…4A). Alternatively, glucose can induce gene transcription via its metabolism through the hexosamine biosynthesis pathway (HBP) (20)(21)(22)(23). To determine the contribution of the HBP to the induction of GPR40 mRNA by glucose, we measured GPR40 mRNA levels in islets treated with the HBP intermediate N-acetyl glucosamine (GlcNAc; 20 mmol/L), which promotes OGlcNAc modification of proteins (also known as O-GlcNAcylation) by increasing UDP-GlcNAc (24).…”

Section: Glucose Stimulation Of Gpr40 Expression Is Mediated By Thementioning

confidence: 99%

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Glucose activates free fatty acid receptor 1 gene transcription via phosphatidylinositol-3-kinase-dependent O -GlcNAcylation of pancreas-duodenum homeobox-1

Kebede

Ferdaoussi

Mancini

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The G protein-coupled free fatty acid receptor-1 (FFA1/GPR40) plays a major role in the regulation of insulin secretion by fatty acids. GPR40 is considered a potential therapeutic target to enhance insulin secretion in type 2 diabetes; however, its mode of regulation is essentially unknown. The aims of this study were to test the hypothesis that glucose regulates GPR40 gene expression in pancreatic β-cells and to determine the mechanisms of this regulation. We observed that glucose stimulates GPR40 gene transcription in pancreatic β-cells via increased binding of pancreas-duodenum homeobox-1 (Pdx-1) to the A-box in the HR2 region of the GPR40 promoter. Mutation of the Pdx-1 binding site within the HR2 abolishes glucose activation of GPR40 promoter activity. The stimulation of GPR40 expression and Pdx-1 binding to the HR2 in response to glucose are mimicked by N-acetyl glucosamine, an intermediate of the hexosamine biosynthesis pathway, and involve PI3K-dependent O-GlcNAcylation of Pdx-1 in the nucleus. We demonstrate that OGlcNAc transferase (OGT) interacts with the product of the PI3K reaction, phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ), in the nucleus. This interaction enables OGT to catalyze O-GlcNAcylation of nuclear proteins, including Pdx-1. We conclude that glucose stimulates GPR40 gene expression at the transcriptional level through Pdx-1 binding to the HR2 region and via a signaling cascade that involves an interaction between OGT and PIP 3 at the nuclear membrane. These observations reveal a unique mechanism by which glucose metabolism regulates the function of transcription factors in the nucleus to induce gene expression.T he pancreatic β-cell plays a central role in the control of glucose homeostasis, and β-cell dysfunction is key to the pathogenesis of type 2 diabetes (1). Insulin secretion from the β-cell is tightly regulated by the coordinated action of hormonal, metabolic, and neural factors, ensuring its maintenance within a narrow physiological range. Among these factors, circulating fatty acids do not initiate insulin secretion but strongly potentiate glucose-stimulated insulin secretion (GSIS) (reviewed in ref.2). The G protein-coupled free fatty acid receptor-1 (FFA1/GPR40) is specifically expressed in pancreatic β-cells and activated by medium-to long-chain fatty acids (3-5). GPR40 plays a major role in fatty-acid amplification of GSIS (3, 4, 6-10) and, as such, is being considered as a potential therapeutic target in type 2 diabetes (11-13). Indeed, a recent report from a phase II clinical trial of the first orally available, selective GPR40 agonist, TAK-875 (13), identified the agonist as a highly effective drug for the treatment of type 2 diabetes (14, 15). However, the mode of regulation of GPR40 in pancreatic β-cells remains essentially unknown.We previously characterized the proximal promoter of the GPR40 gene and showed that the 5′-upstream region contains two evolutionary conserved regions, HR2 and HR3, which display DNase I hypersensitivity in β-cells (16). HR3 contains the...

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Section: Discussionmentioning

confidence: 81%

Section: Glucose Stimulation Of Gpr40 Expression Is Mediated By Thementioning

confidence: 99%

Glucose activates free fatty acid receptor 1 gene transcription via phosphatidylinositol-3-kinase-dependent O -GlcNAcylation of pancreas-duodenum homeobox-1

Kebede

Ferdaoussi

Mancini

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…In mice lacking MafA, reduced insulin 1 and 2 gene transcription, glucose intolerance and development of diabetes mellitus was observed [12]. At least at the beta cell level the transcriptional activity of MafA seems to be regulated by either changes in MafA synthesis or by an enhanced degradation of this protein [11,16,26,48,49]. However, in the present study overproduction of MEKK1 did not decrease the amount of MafA produced in JEG cells (data not shown), arguing against a MEKK1-induced degradation of MafA.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of MafA transcriptional activity and human insulin gene transcription by interleukin-1β and mitogen-activated protein kinase kinase kinase in pancreatic islet beta cells

et al. 2007

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Aims/hypothesis Inappropriate insulin secretion and biosynthesis are hallmarks of beta cell dysfunction and contribute to the progression from a prediabetic state to overt diabetes mellitus. During the prediabetic state, beta cells are exposed to elevated levels of proinflammatory cytokines. In the present study the effect of these cytokines and mitogen-activated protein kinase kinase kinase 1 (MEKK1), which is known to be activated by these cytokines, on human insulin gene (INS) transcription was investigated. Methods Biochemical methods and reporter gene assays were used in a beta cell line and in primary pancreatic islets from transgenic mice. Results IL-1β and MEKK1 specifically inhibited basal and membrane depolarisation and cAMP-induced INS transcription in the beta cell line. Also, in primary islets of reporter gene mice, IL-1β reduced glucose-stimulated INS transcription. A 5′-and 3′-deletion and internal mutation analysis revealed the rat insulin promoter element 3b (RIPE3b) to be a decisive MEKK1-responsive element of the INS. RIPE3b conferred strong transcriptional activity to a heterologous promoter, and this activity was markedly inhibited by MEKK1 and IL-1β. RIPE3b is also known to recruit the transcription factor MafA. We found here that MafA transcription activity is markedly inhibited by MEKK1 and IL-1β. Conclusions/interpretation These data suggest that IL-1β through MEKK1 inhibits INS transcription and does so, at least in part, by decreasing MafA transcriptional activity at the RIPE3b control element. Since inappropriate insulin biosynthesis contributes to beta cell dysfunction, inhibition of MEKK1 might decelerate or prevent progression from a prediabetic state to diabetes mellitus.

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“…The molecular mechanism by which phosphorylated MafA undergoes rapid degradation in response to low glucose is still unknown. Recently, Vanderford et al showed that MafA induction by glucose is mediated by hexosamine biosynthetic pathway [42]. Therefore, O-GlcNAc modification of MafA and/or proteasome subunits may be involved in the regulation of MafA protein abundance.…”

Section: Maf Transcription Factors As Regulators Of Tissue-specific Gmentioning

confidence: 99%

Roles and Regulation of Transcription Factor MafA in Islet .BETA.-cells

2007

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Abstract. Insulin is a critical hormone in the regulation of blood glucose levels. It is produced exclusively by pancreatic islet β-cells. β-cell-enriched transcription factors, such as Pdx1 and Beta2, have dual roles in the activation of the insulin gene promoter establishing β-cell-specific insulin expression, and in the regulation of β-cell differentiation. It was shown that MafA, a β-cell-specific member of the Maf family of transcription factors, binds to the conserved C1/RIPE3b element of the insulin promoter. The Maf family proteins regulate tissue-specific gene expression and cell differentiation in a wide variety of tissues. MafA acts synergistically with Pdx1 and Beta2 to activate the insulin gene promoter, and mice with a targeted deletion of mafA develop age-dependent diabetes. MafA also regulates genes involved in β-cell function such as Glucose transporter 2, Glucagons-like peptide 1 receptor, and Prohormone convertase 1/3. The abundance of MafA in β-cells is regulated at both the transcriptional and post-translational levels by glucose and oxidative stress. This review summarizes recent progress in determining the functions and roles of MafA in the regulation of insulin gene transcription in β-cells.

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Glucose Induces MafA Expression in Pancreatic Beta Cell Lines via the Hexosamine Biosynthetic Pathway

Cited by 56 publications

References 75 publications

Glucose activates free fatty acid receptor 1 gene transcription via phosphatidylinositol-3-kinase-dependent O -GlcNAcylation of pancreas-duodenum homeobox-1

Glucose activates free fatty acid receptor 1 gene transcription via phosphatidylinositol-3-kinase-dependent O -GlcNAcylation of pancreas-duodenum homeobox-1

Inhibition of MafA transcriptional activity and human insulin gene transcription by interleukin-1β and mitogen-activated protein kinase kinase kinase in pancreatic islet beta cells

Roles and Regulation of Transcription Factor MafA in Islet .BETA.-cells

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